Triterpenoid acid derivatives



United States Patent 3,153,038 TRITERPENOID ACID DERIVATIVES Josef Fried, Princeton, and David Walter Rosenthal, New Brunswick, N.J., assignors to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Mar. 28, 1962, Ser. No. 183,014

24 Claims. (Cl. 260-43957) 3 R R R! RI wherein Z is hydrogen, hydroxy or acyloxy and R and R may be hydrogen and together R and R may be oxygen.

ice

(In this application and in the appended claims, whenever, in the formulae set forth herein, a curved line (5) is employed in the linkage of atoms, it is meant to denote that the connected atom may be either in the alpha or beta position, as is determined in the respective compounds involved.)

The preferred acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric, and tert-pentanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (e.g., phenace tic and @phenylpropionic acid),

, the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

Those final products of this invention which are unsubstituted in the 21-position (i.e., Z is hydrogen) are physiologically active compounds which possess progestational activity and thus can be employed instead of progesterone, for example, in the treatment of habitual abortion for which purpose they can be administered in the same manner as progesterone, for example, the dosage being adjusted for the relative potency of the particular steroid. Those final products of this invention which are oxygenated in the 21-position (i.e., Z is hydroxy or acyloxy) are physiologically active compounds which possess mineralocorticoid activity and thus can be employed instead of desoxycorticosterone, for example, in the treatment of Addisons disease, for which purpose they can be administered in the same manner as desoxycorticosterone, for example, the dosage being adjusted for the relative potency of the particular steroid.

The final products ofthis invention wherein Z is hydroxy or acyloxy, are prepared by the process of this invention which entails a number of steps beginning with a triterpenoid acid as a starting materal. By a triterpenoid acid, it is here meant a polymethylsteroid, having a D-ring structure represented by the formula:

' wherein R may be the same or different and may be either I R0l l 0 HO 92 RO Eburicoic acid (A) e 1. R"=CH4;CO

II. R=CH3CH2CO l onion RO R0 III. R:CH3C0 IV. R=CH3C0 RI/O RIIO (D) (E) v. R"=CH CO V I. R=CH3CO I /i i I 0 (F) 0 (G) v11. R=OHaCO IX. 'RzCHsCO VIII. R=H X. R:H

l LiA1H4 l 1.1mm

The final products of this invention, wherein Z'is hydrogen, are prepared by a process of this invention which entails a number of steps beginning with corresponding 21-hydroxy steroid derivatives (Compounds K, L, M, $3120301A (3.111030% and N) as starting materials. These steps are shown by 60 =0 the following equations, wherein Y is 0X0 (0:), or fiacyloxy, and A is lower alkyl or tolyl: V

CHaOH (EHBOH I l l I 70 (0) (P) Y Y XXIX. YzCHaCOO; A=OHa XXXI. Y=CHaCOO; A=CH3 XXX. Y: A=CHa XXXII. Y=O=; Ar-CHs XX. Y=CH3CO0 XXIV. 'Y=CHsCOO XXV. Y=O XXVII. 35:0 75 r n r Q) In the first step of the process of this invention eburicoic acid is converted to its Ii-ester derivative (Compounds A).

ferred esters are those with hydrocarbon carboxylic acids of less than twelve carbon atoms. These are formed by reacting with the acyl chloride or acid anhydride of a hydrocarbon carboxylic acid of less than twelve carbon atoms, such as one of the acids listed hereinbefore.

The 3-ester is then converted to a corresponding ester of 24-keto-A lanostene-2'1-acid (Compounds C). This may be done by ozonolysis of Compounds A and reducing the ozonide formed by treatment with either hydrogen in the presence of a hydrogenation catalyst, such as palladium on charcoal, or an electropositive metal, such as zinc, in the presence of an acid, such as glacial acetic acid, whereby Compounds C are obtained directly. Compounds C can also be obtained in a two-step process by first treating Compounds A with a hydroxylating agent, such as osmium tetroxide, to yield the corresponding 3- ester of 3fi,24,28-trihydroxy-A -eburicene- 21 oic acid (Compounds B), which are new compounds of this invention, and then cleaving the glycol, as by treatment with lead 'tetraacetate to yield Compounds C.

Compounds C are then lactonized by treatment with an acid anhydried and a salt of a strong base and a weak acid, such as sodium acetate in acetic anhydride, to yield a mixture of the oc-lactone (Compounds D) and fi-lactone (Compounds E) of the corresponding S-esters of 3/3-hydroxy-24-keto-A -lanostene-2l-oic acid. These lactones are now compounds of this invention. The reaction pref erably carried out at an elevated temperature, suchas the reflux temperature of the organic solvent employed and the two lactones are separated chromatographically. However, since both the a-lactone and fi-lactone give the same product in the next step of the process of this invention, such separation is not necessary and a mixture of the lactones may be used directly.

Compounds D and E are then dehydrogenated, as by treatment with palladium on characoal at an elevated temperature, to yield the corresponding 3-ester of 313,24- dihydroxy-A -lanostadiene 21 oic acid lactone (Compounds P), which are new compounds of this invention. If desired, the ester can then be saponified in the usual manner, as by treatment with a base such as potassium hydroxide to yield the corresponding free 3/3- hydroxy derivative, and the free 3-hydroxy compound oxidized to the corresponding 3-keto derivative in the usual manner, as by treatment with chromium trioxide.

Compounds F can then be isomerized to the corresponding 3,B,24-dihydroxy-A -lanostadiene-2l-oic acid lactone derivative (Compounds G), which are new compounds of this invention, by treatment with hydrogen chloride in a solvent (e.g., glacial acetic acid).

Compounds F and G are then converted to the final 21- oxygenated pregnene derivatives of this invention by the same series of steps. If a Compound F is employed the final products and all intermediates contain a double-bond in the 8,9-position. If a Compound G is employed, the final products and all intermediates contain a doublebond in the 7,8-position.

In the first step of this process, compounds F and G are reduced by treatment with lithium aluminum hydride to yield a corresponding 3,8,21-dihydroxy-A -lanostatriene (Compouns H) and 35,2l-dihydroxy-A' lanostatriene (Compounds J derivatives, respectively. These compounds can be converted to their 2l-ester (or 3,2l-diester, if a free 3-hydroxy compound is initially produced) derivatives by the usual acylation procedure. The preferred acylating agents are the acyl chlorides and acid anhydrides of the hydrocarbon carboxylic acids of less than twelve carbon atoms mentioned hereinbefore. All Compounds H and J are new compounds of this invention.

Compounds H and I are then oxidized, as by treatment with ozone and reduction of the ozonide formed, to yield 3/3,21-dihydroxy-4,4,l4u-trimethyl A' -Sa-pregnene 20- one (Compounds L), respectively, or monor or diester of each of these depending on the degree of esterification of the starting material. Moreover, if a diester is initially formed, it can be selectively saponified to the 3-monoester by treatment with potassium carbonate and if a dihydroxy compound is initially formed, it can be selectively esterified to the 2l-monoester by treatment With the desired acid anhydride in pyridine. Thus, all combinations of Compounds K and L, containing two free hydroxyl groups, a 3-monoester group, a 21-monoester group, or a 3,2l-diester group can be obtained. Compounds K and L are new compounds of this invention.

Compounds K and L, containing a free 3,8-hydroxy group, can then be oxidized in the usual manner, as by treatment with chromium trioxide, to yield the final products of this invention, which contain either a 21-hydroxy group or aZl-acyloxy group (Compounds M and N).

If a 2l-unsubstituted compound is desired (Compounds S and T), a Compound K, L, M or N, containing a free 2l-hydroxy group, is acylated by treatment with an organic sulfonyl chloride, such as a lower alkanesulfonyl chloride (e.g., mesyl chloride) or tosyl chloride, to yield the corresponding 2l-sulfonic acid ester (Compounds 0 and P), which are new compounds of this invention.

Compounds 0 and P are then converted to their corresponding 2l-iodo derivatives (Compounds Q and R, respectively) by treatment with an alkali metal iodide (e.g., sodium iodide), preferably at an elevated temperature. Compounds Q and R are new compounds of this invention.

Compounds Q and R are then reduced, as by treatment with sodium bisulfite, to yield the final products of this invention which are unsubstituted in the 2l-position (Compounds 8 and T). If a 3fl-hydroxy or 35-acyloxy derivative is initially formed it may be oxidized to the corresponding 3-keto derivative (after saponification of the 3-ester group, if present) to yield the final 3-keto compounds of this invention. The procedures hereinbefore set forth with regard to the treatment of eburicoic acid to obtain the final products of this invention, may

I l CH3 H O CQC Ha Tumulos'i'c acid XDV. RzCHsCO be likewise applied to other triterpenoid acids to give like results. Thus, where tumulosic acid is employed as the starting material, the results set forth in the following equations are obtained:

XLVI. R=CHsCO CQC Ha XLIX. R=CHaCO L. RIH

for eburicoic acid conversion.

(L Roam.

CH3 CH3 CH: CH; 7

(Q') LXXIV. R:H 'LXXVI'I. R:H

LXXV. -RO== LXXVIII. 130:0:

Thus, following the same procedures outlined above in the case of eburicoic acid, tumulosic acid is first converted to its 3,16 ester derivative (Compounds A), these being ozonized and reduced to a corresponding ester of 24-keto-A -lanostene-2l-oic-acid (Compounds B). Compounds B are then lactonized to yield a mixture of a-lactone (Compounds C) and l3-lactone (Compounds D) of the corresponding 3,16 esters of 3 5,160: dihydroxy 24- keto-M-lanostene-Zl-oic acid. These lactones are new.

then converted to the final Zl-Oxygenated pregnene derivatives of this invention by the same series of steps. Compounds E and F are reduced to yield the corresponding 3 B,160c,21 trihydroxy-A lanostatriene (Compounds G) and 3,8,16oc,21 trihydroxy A' lanostatriene (Compounds H) derivatives, respectively. Compounds G and H are then oxidized to yield 3fi,16oc,21- trihydroxy 4,4,14oc trimethyl A a pregnene one (Compounds J) and 3,8,16u,2ltrihydroxy-4,414utrimethyl A 5a pregnene-ZO-one (Compound K), respectively. These are also new compounds of this invention. Compounds J and K can then be oxidized to form the final products of this invention, which contain either a Zl-hydroxy group or a 21-acyloxy group (Compounds L and M). To obtain the ZI-unsubstituted compounds (Compounds N, 0', P and Q), a Compound J K L or M is acylated with a sulfonic acid halide, the resulting compound converted to the corresponding 21-iodo derivative and the iodo derivative is then reduced to yield the 2l-unsubstituted Compounds N, O, P and by practicing the same procedure as outlined above The same process as hereinbefore set forth is applicable wherein the starting material is'pinicolic, elemolic, 3-epi-elemolic, and elemonic acids.

When the starting material employed in the practice of this invention is polyporenic, dehydroeburicoic, and other like acids having two double bonds in the 7 and 9(11) positions, there is a slight variation in the procedure. In the processing of eburicoic, tumulosic, and like acids, isomerization can be achieved by treating Compounds F and E set forth above, with hydrogen chloride in a solvent. Since such results are not possible in the case of the 7,9(11) double bonded acids, this step is bypassed in their processing. However, all other steps of the process remain the same.

For example, if polyporenic acid C is employed as the starting material of this invention, the following equations represent the process set forth hereinbefore:

. l l CH:

CH3 CH3 Eolyporentc acid 0 CH: II

nooo

CH3\GH3 s 3 LXXX. PJ' CHaCO 1 T? (3H2 (IJH Z :0 3:0

Elemonic acid derivative (IIH Z C.=O

Dehydroelemonic acid derivative The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 Eburicoic Acid 3-Propi0nate (II) To a solution of 10 g. of eburicoic acid in 50 ml. of anhydrous pyridine is added 10 ml. of propionic anhydride and the mixture is allowed to remain at room temperature for 18 hours. Five grams of ice is then added and 30 minutes later the mixture is diluted slowly with 250 ml. of ice and water. The resulting precipitate is filtered, Washed thoroughly with water, dried in vacuo and recrystallized from 95% alcohol yielding pure eburicoic acid 3-propionate (11).

Similarly, by substituting other acid anhydrides or acyl halides for the propionic anhydr-ide in the procedure of Example 1, the corresponding S-esters are formed. Thus, butyric anhydride and benzoyl chloride yield the 3-butyrate and 3-benzoate of eburicoic acid, respectively.

EXAMPLE 2 3,8-Acetoxy-24-Ket0A -Lan0stene-21-Oic Acid (IV) Through a solution of 15 g. of eburicoic acid 3-acetate (I) in a mixture of 150 ml. of chloroform and 150 m1. of ethyl acetate, cooled in a Dry Ice-acetone bath, is passed 26.2 1. of ozone (1 mole of ozone contained in .89 1. of oxygen). The resulting solution is allowed to Warm to room temperature and then added to a suspension of 975 mg. of pre-reduced 5% palladium on charcoal catalyst in 50 ml. of ethyl acetate. 550 ml. of hydrogen is taken up rapidly, following which the solution is filtered and the filtrate evaporated to dryness in vacuo.

Alternately the ozonide can be decomposed with zinc in V acetic acid as follows: The ozonolysis mixture obtained from 50 g. of eburicoic acid 3-acetate in 50 ml. of chloroform and 500 ml. of ethyl acetate, is allowed to warm up to when it is diluted with 50 ml. of glacial acetic acid. Powdered zinc is then added in portions with stirring and the temperature allowed to rise to A total of 25 g. of zinc is required. After 2 /2 hours the reaction mixture is filtered and the zinc and zinc salts Washed thoroughly with ethyl acetate. The ethyl acetate-chloroform filtrate is washed thoroughly with Water, dried over sodium sulfate and evaporated to dryness in vacuo. A total of about 56 g. of the crude keto acid (1V) is obtained.

The acid (IV) is obtained in pure form by chromatography on neutral alumina. For this purpose a solution of 14 g. of the crude acid is dissolved in 50 ml. of benzene and charged to the column containing 280 g. of

alumina. 50% chloroform-benzene (9 l.) elutes about 1.9 g. of pure acid melting at about 234236, which is followed by about 112 g. of acid when the eluant is changed to 75% chloroform in benzene (3 1.). An additional 1.3 g. of pure acid is obtained with chloroform (5 1.). The column is then stripped with 5% acetic acid in chloroform (2 l.) which elutes about 10.4 g. of crude material which is dissolved in 100 ml. of benzene and rechromotographed on 200 g. of silica gel. Elution with benzene (750 ml.) gives about 4 g. of amorphous mate rial which is followed by crystalline acid (about 2.4 g.) when the eluant is changed to chloroform (8 1.). The pure acid (IV) has the following properties: M.P. 23.6- 238"; [a] +52 (c., .49 in ch1f.);

x 5.78 and 5.9%; x 5.83-5.90; 8.05, 9.76 and max. max.

Analysis.-Calcd. for C H O (514.72): C, 74,67; H, 9.79. Found: C, 74.64; H, 9.54.

EXAMPLE 3 Polyporenic acid C 16-acetate (LXXIX) is treated in accordance with the procedures set forth in Example 2 above yielding 16a-acetoxy-3,24-diketo-dehydroeburicoic acid (LXXX).

EXAMPLE 5 3 fl-A cet0xy-24,2 8-Dihydroxy-A -Eburicene-Zl -Oic Acid (III To a solution of 2 g. of eburicoic acid 3-acetate (I in 20 m1. of benzene and 2 ml. of pyridine is added dropwise a solution of 1 g. of osmium tetroxide in 10 ml. of henzene. Addition is complete in 1 hour and the reaction mixture is allowed to remain at room temperature for an additional 4 hours. The resulting dark solution is diluted with 76 ml. of dioxane and saturated with hydrogen sulfide for 15 minutes. The resulting suspension is filtered with the aid of Celite and the filtrate evaporated to dryness. The resulting residue (about 2.1 g.) is triturated with acetone leaving about 1.5 g. of the dihydroxy acid (III) melting at about 238-242". Recrystallization of this material from ethanol furnishes the pure dihydroxy acid possessing the following properties: M.P. about 246-284";

A233, 2.95, 5.80, 6.05 and 8.00-8.10n

Analysis.-Calcd. for C H O C, 72.49; H, 9.92. Found: C, 71.76; H, 9.92.

EXAMPLE 6 3,8-Acetoxy-Z4-Ket0-A -Lanostene-21-Oic Acid (IV) A solution of 1.17 g. of the 24,28-dihydroxy acid (111) in 200 ml. of .0108 molar lead tetraacetate solution in glacial acetic acid is allowed to stand at room temperature for 35 minutes. A few drops of ethylene glycol are then added to reduce the excess lead tetraacetate and the solution is concentrated in vacuo and diluted with water. The resulting suspension is extracted with ethyl acetate and the ethyl acetate extract washed several times with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting crude produce (about 1.07 g.) on recrystallization from acetone furnishes about 700 mg. of the pure keto acid IV possessing the following properties: M.P. about 225-227"; [M +50 (c., .43 in chlf.).

Analysis.-Calcd. for (3 1-1 0 C, 74.67; H, 9.79. Found: C, 74.32; H, 9.50.

This acid is identical in all respects with the product obtained in Example 2. l

3% EXAMPLE 7 3B Acetoxy 24 Hydroxy A8123 Lanostadiene 21- Oic Acid Lactone (a-Lactone) (V) and 3fl-Acetoxy- 24 Hydroxy A8124 Lanostadiene 21 Oic Acid Lactone (fl-Lactone) (VI) To a solution of 15.4 g. of 3fl-acetoxy-24-keto-A -lanostene-21-oic acid (IV) in 150 ml. of acetic anhydride is added 3.75 g. of anhydrous sodium acetate and the resulting suspension is heated under reflux for 10 hours. Upon cooling, the acetic anhydride solution is decanted from the sodium acetate and the latter washed thoroughly with benzene. The combined acetic anhydride-benzene solutions are evaporated to dryness in vacuo, the residue redissolved in benzene and filtered from the precipitated sodium acetate. The clear benzene solution is evaporated to dryness leaving a mixture of the C- and fi-enol lactones (V and VI) (about 15.1 g.). Separation is achieved by chromatography on neutral alumina as follows: The total residue is dissolved in 50 ml. of benzene and 50 ml. of hexane and charged to a column containing 300 g. of neutral alumina. Elution with 250 ml. of benzene-hexane (1:1) produces about 3.1 g .of crude crystalline 3B- acetoxy-24-hydroxy-A -lanostadiene-21-oic acid is lactone (ix-lactone) (V), which after crystallization from 95% ethanol is analytically pure and has the following properties: M.P. about 169-171"; [041 +37;

A, 3l?5.69, 5.78, 5.93, (weak), 8.05, 12.05, 12.62, and 13.30,.

The 12.05 and 12.63 bands are diagnostic for the a-lactone and are absent in the ,B-lactone.

Analysis.-Calcd. for C H O (496): C. 77.37; H, 9.73. Found: C, 77.41; H, 9.82.

Continued elution of the alumina column with benzene (8 1.) produces a total of about 4 g. of material in 12 fractions, all of which melt between 150-160" and represent a mixture of the ocand B-lactones. Rechromatography of this mixture is necessary to obtain the pure fl-lactone. For the purpose all of the fractions are combined (4 g), dissolved in 20 ml. of benzene and 80 ml. of hexane and charged to a column of 120 g. of neutral alumina. Elution with benzene-hexane (1:4) produces, in the first 500 ml., about 827 mg. of the pure zit-lactone (V) which is followed by elution with the same solvent mixture (5.5 l.) and on elution with benzene-hexane (1:1, 2 l.) by a total of about 2.9 g. of material, representing a mixture of aand ,B-lactone melting at about 158-160". Continued elution of the column with benzene (9 1.) yields a total of about 1.2 g. of material which after recrystallization ethanol constitutes pure 3fl-acetoxy-24-hydroxy-A lanostadiene-Zl-oic acid lactone (Ii-lactone) (VI) (about 404 mg.) possessing the following properties: M.P. about 190-191"; [04 +64 (C, .87 in chlf.); 23?

and

The 11.80 1. band is absent in the a-lactone.

Analysis.-Calcd. for C H O (496.70): C, 77.37; H, 9.73. Found: C, 77.56; H, 9.73.

EXAMPLE 8 Treating the 3,6,16oe-diacetoxy-24-keto-M-lanostene-Z1- oic acid (XLIV) obtained in Example 3, in accordance with the procedures set forth in Example 7 above, yields 3 ,8,16a-diacetoxy-24-keto-A -lanostadiene 21 oic acid lactone (aalactone) (XLV) and 3 8,16a-diacetoxy-24-hydroxy-A -24-lanostene-2l-oic acid lactone (fi-lactone) (XLVI).

EXAMPLE 9 Treating the 16a-acetoxy-3,24-diketo-dehydroeburicoic acid (LXXX) obtained in Example 4 above, according to the procedure set forth in Example 7, yields 16a-acetoxy- 3,24-diketo-A -lanostatriene-2l-oic acid lactone (oclactone) (LXXXI) and 16a-acetoxy-3,24-diketo-A' lanostatriene-2l-oic acid lactone ([i-lactone) (LXXXII).

5.70, 5.79, 5.97, (weak), 8.08, 11.50, 11.50, 11.80 V

A suspension of 180 mg. of 10% palladium on charcoal in 25 ml. of p-cymene is distilled until approximately 3 ml. of solvent have been removed. The final temperature of the vapors is over 170. 250 mg. of the thoroughly dried 06-61101 lactone (V) is then added and the resulting suspension heated under reflux with stirring for 2 hours under a blanket of nitrogen. The mixture is cooled, filtered and the solvent removed in vacuo. The residual crystalline material on recrystallization from absolute ethanol furnishes the pure ot-pyrone (VI) in about 75% yield possessing the following properties: M.P. about 228228.5; [M 114 (chli);

A33}, 305 m e =8,850); A221? 5.79, 5.90, 6.11, 6.35, 8.95, 11.90 and 1269a Analysis.Calcd. for C H O (494.68): H, 9.37. Found: C, 77.77; H, 9.43.

When the B-enol lactone (VI) is substituted for the alactone (V) in Example 6 and the reaction time is prolonged to 6 hours, the pyrone (VII) is obtained in about 60% yield. Moreover, when a mixture of aand 8-enol lactones (V and VI) g.) is dehydrogenated with 80 g. of 10% palladium on charcoal in 700 ml. of p-cymene for 6 hours, about 50 g. of the pure ct-pyrone (VII) of M.P. about 226-228 is obtained.

Furthermore, if another ester of eburicoic acid, such as the 3-propionate (II), the 3-butyrate or the 3-benzoate is substituted for the 3-acetate in the procedures of either Example 2 or Example 5 and the procedures of Examples 2 through 10 are carried out, the corresponding 3- esters are obtained.

EXAMPLE 1 1 Treating the 3,8,16a-diacetoxy lactones (XLV and XLVI) obtained in Example 8, in accordance with the procedure set forth in Example 10 above, yields 35,161 diacetoxy 24-hydroxy-A -lanostatriene-2l-oic acid lactone (e py-rone) (XLVII).

EXAMPLE l2 Treating the 16ot-acetoxy lactones (LXXXI) and (LXXXII) obtained in Example 9, in accordance with the procedures set forth in Example 10 above, yields 16ot-acetoxy-3,24-diketo-A' lanostatetraene 21 oic acid lactone (a-pyrone) (LXXXIII).

EXAMPLE 13 3,8,24-Dihydr0xy-A -Lan0statriene-Oic Acid Lactone (VIII) To a solution of 510 mg. of potassium hydroxide in 10 ml. of ethylene glycol is added 73 mg. of the finely ground a-pyrone acetate (VII). The suspension is stirred and immersed in an oil bath held at a temperature of After 5 minutes there results a clear pale yellow solution which is heated for an additional 4 minutes and then cooled. 25 ml. of water is added and the mixture extracted with ether. The ether extract is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo. About 60 mg. of crystalline residue is obtained which on recrystallization from acetone furnishes long needles of the apyrone 3-ol (VIII) possessing the following properties: M.P. 254255;

A312 303 my (e=9,000); 6.33, 11.85 and 12.62

Analysis.-alcd. for C H O (452.65): C, 79.60; H,

9.80. Found: C, 79.50; H, 9.83.

EXAMPLE 14 Treating the a-pyrone diacetate (XLVII) obtained in Example 11, according to the procedures set forth in ANuiol max.

221 Example 14, yields 3p,16a,24-trihydroxy-A -lano statriene-Zl-oic acid lactone (XLVIII).

EXAMPLE 15 Treating the OL-PYI'OIIB acetate (LXXXIII) obtained in Example 12, according to the procedures set forth in Example 14, yields 16a-hydroxy-3,24-diketo-A' 1anostatetraene-2l-oic acid lactone (LXXXIV).

EXAMPLE 16 24-Hydroxy-3-Keto-A -Lanostatriene-Zl Oic Acid Lactone To a solution of 95 mg. of 3 8,24-dihydroxy-A lanostadiene-Zl-oic acid lactone (VIII) in 3 ml. of acetone is added 1 ml. of a 90% aqueous acetone solution of 20 mg. of chromium trioxide and 32 mg. of concentrated sulfuric acid. After 10 minutes methanol is added to reduce excess chromium trioxide and the solution is diluted with Water and extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue on recrystallization from acetonitrile produces the analytically pure 3-ketone possessing the following properties: MP. about 230-232";

hfigif 5.87, 6.08, 6.30.12.02 and 1263 Analysis.Calcd. for C H O (415.63): C, 79.95; H, 9.39. Found: C, 80.21; H, 9.54. EXAMPLE 17 3/3-Acetoxy-24-Hydroxy-A' -Lanstatriene- 21 -OiC Acid Laczone (IX) A solution of S g. of 3p-acetoxy-24-hydroxy-A lanostatriene-21-oic acid lactone (VII) in 350 ml. of glacial acetic acid is saturated with dry hydrogen chloride gas first at 10 and finally as more'HCl dissolves at 0. This requires a total of 30 minutes. The solution is maintained for an additional hour at 0 and then evaporated to dryness in vacuo. The resulting crystalline residue on recrystallization from 95% ethanol and chloroform furnishes about 3.75 g. (75%) of a mixture consisting largely of the A and some of the A -isomer, M.P. 229- 231; [001 135 (chlf). A sample of this product is chromatographed on acid-washed alumina using a 100:1 ratio of alumina to sample. After elution of the A -isomer with chloroform-benzene (1: 8) the main fraction is eluted with pure chloroform to give the pure A isomer (IX), which on recrystallization from methanol has the following properties: M.P. 230-230.'5; -144 (chlf.).

Analysis.-Calcd. for 0 1-1 0 (494.68): C, 77.69; H, 9.37. Found: C, 77.92; H, 9.40.

mux.

essentially identical with the A -isomer VII except for the presence of a medium band at 12.05 11, which is weak in the latter.

EXAMPLE 18 Treating the oc-pyrone diacetate (XLVII) obtained in Example 11 according to the procedures set forth in Example 17 yields 3B,16a-diacetoxy-24-hydroxy-A lanostatriene-Zl-oic acid lactone (XLIX).

EXAMPLE 19 3 {3-H ydroxy-24-Ket0-A' -Lanostatriene-21 Oic Acid Lactone (X) Following the procedure of Example 17 but substituting g. of 3B-hydroxy-24-keto-A -lanostatriene- 21-oic acid lactone (VIII) for the acetate (VII), 3p-hy droxy-24-keto-A -lanostatriene 21 oic acid lactone (X) is obtained.

22 EXAMPLE 20 36-21-Dihydr0xy-A -Lan0statriene (XI) A solution of 5 g. of the a-pyrone (VII) in 210 ml. of freshly distilled tetrahydrofuran is added over a 15- minute period to a refluxing solution of 5 g. of lithium aluminum hydride in 125 ml. of tetrahydrofuran with stirring under a blanket of nitrogen. Reflux is continued for an additional 2 hours and the solution is cooled to room temperature. Saturated sodium sulfate solution is then added carefully until all the lithium aluminum hydride is decomposed, after which the reaction mixture is shaken with several 200 ml. portions of benzene and the resulting extracts decanted from the inorganic salts until all the organic material is extracted. The benzene-tetrahydrofuran solution is dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue (about 4.6 g.) is dissolved in ml. of benzene and the solution chromatographed on 100 g. of neutral alumina washing the column with 800 ml. of benzene to remove some impurities. The desired trienediol (X1) is obtained by elution with 2800 ml. of 10% chloroform in benzene. The combined eluates are evaporated to dryness and recrystallized from ether, which results in about 2.06 of the pure trienediol XI possessing the following properties:

M.P. about 166-168; a +68 (chlf);

.;1g-. 24.4 m (e=32,800): my 3.10, 9.71, and 10.4.0

Treating the ot-pyrone (XLVII) obtained in Example 11, according to the procedures set forth in Example 20, yields 3,6,16a,2l-trihydroxy-A -lanostatriene (LI).

EXAMPLE 22 Treating the a-pyrone (LXXXIII) obtained in Example 12, according to the procedures set forth in Example 20, yields 3 16a,21-trihydroxy-A -1anostatetraene (LXXXV).

EXAMPLE 23 3 [3,21 -Diacet0xy-A -Lan0statriene (XII) ill}. 242 m (e=32,100);

max.

Analysis.-Calcd. for C H O (524.75): C, 77.82; H, 9.99. Found: C, 77.75; H, 10.01.

Similarly, if other acylating agents, such as propionic anhydride, butyric anhydride and benzoyl chloride, are substituted for the acetic anhydride in the procedure of Example 12, the corresponding diesters are formed.

EXAMPLE 24 Treating the triene (LI) obtained in Example 21, in accordance with the procedures of Example 23, yields 3p,16,21-triacetoxy-A -lanostatriene (LII).

23 EXAMPLE 25 Treating the tetraene (LXXXV) obtained in Example 22, in accordance with the procedures of Example 23, yields 3,16oc,2l triacetoxy-Y -lanostatetraene (LXXXVI).

EXAMPLE 26 3&2] -Dihydroxy-A -Lanstadiene 46 mg. of the trienediol (X1) is hydrogenated in ml. of absolute ethanol with mg. of 5% palladium on charcoal. Within 6 minutes a sharp break corresponding to the uptake of 1 mole equivalent of hydrogen occurs, at which time the reaction is interrupted. The catalyst is filtered off and the solvent evaporated in vacuo. The dihydro derivative crystallizes from methanol containing a trace of water and has the following properties: mp. about 145147.

Analysis.Calcd. for C H O (442.70): C, 81.39; H, 11.38. Found: C, 81.35; 11.41.

EXAMPLE 27 3fi-Acet0xy-21 -Hydr0xy-A -Lan0statriene (XIII) To a solution of 50 mg. of 3,8,2l-dihydroxy-A lanostatriene (XII) in 20 ml. of methanol is added with stirring under nitrogen 0.2 ml. of 10% oxygen-free potassium carbonate. After two hours at room temperature 0.02 ml. of glacial acetic acid is added and after the addition of Water the methanol is removed in vacuo. The mixture is extracted with chloroform, the chloroform extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue of the 21-hydroxy compounds XIII is recrystallized from acetone-hexane.

EXAMPLE 28 Treating the triene (LII) obtained in Example 24, in accordance with the procedures set forth in Example 27, yields 3fi-acetoxy-16a,21dihydrOXy-N ZB-lanostatriene (LIII).

EXAMPLE 29 Treating the tetraene (LXXXVI) obtained in Example 25, in accordance with the procedures set forth in Example 27, yields 3-acetoxy-1611,21-dihydroxy-A' lanostatetraene (LXXXVII).

V 7 EXAMPLE 30 3 6,1 6ot-Dihydr0xy-21-A cezoxy-A -Larz0statriene The 3,8,16a,21-trihydroxy A lanostatriene (1 mmole) (LI) obtained in Example 21, is monocetylated with a solution of 1.1 mmole of acetic anhydride in pyridine at room temperature. The reagents are evaporated in vacuo and the crystalline residue is recrystallized from methanol. After two crystallizations, 3,8,16ot-dihydroxy 21 acetoxy-A -lanostatriene is obtained (LIV).

EXAMPLE 31 aim-nih dmx -zz-Awax -Aw w w- Lanostateraene Substituting the 3,16a,21-trihydroxy- A lanostatetraene (LXXXV) obtained in Example 22 for the 3 ,8,16ot,21-trihydroxy-A -lanostatriene of Example 30, 3,1.6a-dihydroxy 21 acetoxy-A' -lanostatetraene (LHXVII) is obtained by following the procedures of Example 30.

EXAMPLE 32 3,8,2] -Dihya'r0xy-A -Lan0statriene (XI V) Following the procedure of Example 20, but substituting 5 g. of the oc-pyrone (IX) for the a-pyrone (VII), 35,2l-dihydroxy-A -lanostatriene (XIV) is obrained.

313,21-Diacet0xy-A -Lan0statriene (XV) Following the procedure of Example 23, but substituting 200 mg. of the triene (XIV) for the triene (XI), 3,8,2l-diacetoxy-A' lanostatriene (XV) is obtained.

EXAMPLE 35 Treating the 3,8,l6rx,21-trihydroxy-A -lanostatriene (LV) obtained in Example 33 according to the procedure set forth in Example 27 yields 3p,16ot,21-triacetoxy-A' -lanostatriene (LVI).

EXAMPLE 36 Treating the 3fi,16oc,21 triacetoxy- A' lanostatriene (LVI) obtained in Example 35, according to the procedures set forth in Example 27 yields 3/3-acetoxy- ,21-dihydroxy-A -lanostatriene (LVII).

EXAMPLE 37 3,B-Acet0xy-21 -Hydr0xy-A' -Lan0statriene (XVI) Following the procedure of Example 27 but substituting 50 mg. of the triene (XV) for the triene (XII), 3,8- acetoxy-2l-hydroxy-A' -lanostatriene (XVI) is obtained.

EXAMPLE 38 Treating the 35,160:,2l-trihydroxy-A -lanostatriene (LV) obtained in Example 33, according to the pro cedure set forth in Example 30, yields 3B,16a-dihydroxy- 21-acet0xy-A -lanostatriene (LVIII).

EXAMPLE 39 3 6,21 -Dihydroxy-4,4,1 4 ot-Trin1ezhyl-A -5 a-Pregnene-ZO- one (XVII) A solution of 232 mg. of the trienediol (XI) in 40 ml. of ethyl acetate is ozonized at 20 with 2.1 mole equivalents of ozone (.81 liter of gas per mmole of ozone). The resulting ozonide is decomposed at room temperature by the addition of .4 ml. of glacial acetic acid and 2 g. of zinc dust (in portions). The mixture is stirred for 2% hours when it no longer gives a positive test with potassium iodide starch reagent. The solution is filtered and washed with sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. A crystalline residue remains, which on recrystallization from methanol furnishes about 77 mg. of the ketal (XVII) melting at about 214-216". Crystallization from the same solvent furnishes the pure compound possessing the following properties: Ml. about 220221 [a] +113 (CHCl ANuiol 10.23. Found: C, 76.85; H, 10.20.

EXAMPLE 40 Treating the 35,16ot,21-trihydroxy-A -lanostratriene (LI) obtained in Example 21, according to the procedure set forth in Example 39, yields 3,B,16a,2l-trihydroxy-4,4,14u-trimethyI-A -Soz-pregnene-2O-one (LIX).

EXAMPLE 41 to the procedures set forth in Example 39, yields 3,16a,21-

trihydroxy-4,4,14a-trimethyl-A' 50c pregnadiene-ZO- one (LXXXIX).

f t EXAMPLE 42 3 [3,21 -Diacetoxy-4,4,14a-TrimethylA -5oc-Pregnene- ZO-One (XVIII) 100 mg. of the trienediol diacetate (XII) is dissolved in 10 ml. of ethyl acetate and ozonized at 25 with 3 mole equivalents of ozone. To the resulting solution are added at room temperature a few drops of acetic acid and then portionwise a total of 1 g. of zinc dust until a negative starch iodide test is observed, which requires about 3 hours. The mixture is then filtered, Washed with a saturated salt solution, dried over sodium sulfate and evaporated to dryness in vacuo. A crystalline residue (about 82 mg.) is obtained, which on recrystallization from methanol yields about 37 mgQof material melting at about 182-184". Further crystallization from menthanol furnishes analytical material possessing the following properties: M.P. about 187-1885"; +101 (0., .22 in chlf.);

x23 5, 5.73 (shoulder), 5.78, 8.03, 9.30, 9.70, and 9,88

Analysis.Calcd. for C H O (458.61): C, 73.32; H, 9.23. Found: C, 73.10; H, 9.02.

EXAMPLE 43 Treating the 3B,16a,2l-triacetoxy-A -lanostatriene (LII) obtained in Example 24, according to the procedure set forth in Example 42, yields 35,16u,21- triacetoXy-A -Saregnene-ZO-One (LX) EXAMPLE 44 Treating the 3,16a,2l-triacetoxy-A' -lanostatetraene (LXXXVI) obtained in Example 25, according to the procedures set forth in Example 42, yields 3,16a,2ltriacetoxy 4,4,14a-A 5a pregnadiene 20 one (LXL).

EXAMPLE 45 3B-Hydr0xy-21 -A-cetxy-4,4,14ot-TrimethyLA -a- Pr'egnene-ZO-One (XIX) 17.3 mg. of the diol (XVII) is monoacetylated with 2 ml. of'a. solution of acetic anhydride in pyridine containing 1.1 moleequivalent of acetic anhydride at room temperature for 18 hours. The reagents are evaporated in vacuo and'the crystalline residue is recrystallized from methanol. After two crystallizations the 21-monoacet-ate (XIX) is obtained possessing the following properties:

M.P. about 191-192".

Analysis.Calcd. for C H O (416.58): C, 74.97; H, 9.70. Found: C, 74.97; H, 9.48.

EXAMPLE 46 EXAMPLE 47 Treating the 3,16a,21 trihydroxy 4,4,l4a-trimetl1yl- A -5a-pregnadiene-20-one (LXXXIX) obtained in Example 41 with 2.1 mole equivalents of acetic anhydride in pyridine according to the procedure set forth in Example 45, yields 16ot,21-diacetoxy-3-hydroxy-4,4,l4ot-trimethyl-A -5ot-pregnadiene-20-one.

EXAMPLE 48 3fl-Acet0xy-21-Hydroxy-4,4,14a-TrimeIhyZ-A -Sa- Pregnene-ZO-One (XX) To a solution of 45 mg. of the diacetate (XVIII) in 20 ml. of methanol is added with stirring under nitrogen .2 ml. of oxygen-free potassium carbonate. After 2 hours at room temperature .02 ml. of glacial acetic acid is added and after the addition of water the methanol is removed in vacuo. The mixture is extracted with chloroform, the chloroform extract washed with Water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting crystalline residue after recrystallization from methanol furnishes about 34 mg. of the pure 3-nionoacetate (XX) possessing the following properties: M.P. about 202-204; [M +93 (c., .38 in chlf.)

Analysis.Calcd. for C H O (416.58): C, 74.96; H, 9.68. Found: C, 75.14; H, 9.64.

EXAMPLE 49 Treating the 3B,16a,21-triacetoxy-A -5a-pregnene-20- one (LX) obtained in Example 43, in accordance with the procedure set forth in Example 48, yields a mixture of 35 acetoxy t,21 dihydroxy-4,4,14-trimethyl-A -5apregnene-ZO-one (LXI) and 3B,l6a-diacetoxy-2l-hydroxy- 4,4,l4ot-trimethyl-A -5m-pregnene-ZO-One (LXIII), which is separated by chromatography on silica gel.

EXAMPLE 50 Treating the 3,1601,2ll1'l8.C6tOXy-A -5 ot-pregnadiene- 20-0ne (LXL) obtained in Example 44 according to the procedures set forth in Example 48 yields a mixture of 3 .aceto xy 16a,2l-dihydroxy-4,4,14a-trimethyl-A' 50-pregnadiene-20-one (LXLI) and 3,16ot-diacetoxy-20, 21 hydroxy-4,4,14ot-trimethyl-A' -Sa-pregnadiene-20- one (LXLIII) which is separated into the individual components by chromatography on silica gel.

EXAMPLE 51 EXAMPLE 53 35,21-Dihydr0xy-4,4,14a-TrimelhyLN-Sa-Pregnene- 20-0116 (XXI) Following the procedure of Example 39 but substituting 232 mg. of the trienediol (XIV) for the trienediol (XI), 313,21-dihydroxy-4A,l4a-trimethyl-A' -5ot-pregnene- ZO-one (XXI) is obtained.

EXAMPLE 54 EXAMPLE 5 6 Treating the 3,3,16a,21-triacetoxy-A -lanostatriene (LVI) obtained in Example 35, according to the procedures set forth in Example 42 yields 3fi,16oz,2l-triacetoxy-4,4,14u-trimethyl-A -5 c -pre gnene-ZO-one (LXV) EXAMPLE 5 7 3 ,B-H ydroxy-Zl -A cet0xy-4,4,I 4u-Trimethyl-A' 5 a-Pregnene-ZO-One (XXIII) Following the procedure of Example 45 but substituting 17.3 mg. of the diol (XXI) for the diol (XVII),

EXAMPLE 5 8 Treating the 3B,l6tx,21 trihydroxy 4,4,l4u-trimethyl- A' -Sar regnene-ZO-One (LXIV) obtained in Example 54 with 2.1 mole equivalents of acetone anhydride in pyridine according to procedures set forth in Example 45 yields l6a,2l-diacetoxy-3/3-hydroxy 4,4,14u-trimethyl-A 5u-pregnene-20-one (LXVIII).

EXAMPLE 59 Following the procedure of Example 48 but substituting 45 mg. of the diacetate (XXII) for the diacetate (XVIII), 3,8 acetoxy 21 hydroxy 4,4,14-a trimethyl-A -Sapregnene-ZO-one (XXIV) is obtained.

EXAMPLE 60 Treating the 3,8,l6ct,2l-IrlaCBIOXYA-fl,l4o!rtflmthyl-A Sa-pregnene-ZO-Qne (LXV) obtained in Example 56, ac cording to the procedures set forth in Example 48 yields a mixture of 3,8-acetoxy 1604,21 dihydroxy-4,4,14a-trimethylA' Sa-pregnene-ZO-One (LXVI) and 3/3,16 x acetoxy-21 hydroxy 4,4,14a-trimethyl-A -5a-pregnene-ZO- one (LXVIII) which is separated into individual components'by chromatography on silica gel.

EXAMPLE 61 2J-A cetxy-4,4,I4a-Trimethyl-A -ot-Pregnene- 3,20-Dz'one (XXVI) EXAMPLE 62 Treating the 3,6,l6tx-dihydroxy-21-acetoxy-4,4,14u-trimethyl-A -Stx-pregnene--one (LXII) obtained in Example 51, according to the procedures set forth in Example 61, yields 2l-acetoxy-4,4,14a-trimethyl-A -5a.-pregnene- 3,16,20-trione (LXIX).

EXAMPLE 63 Treating the 3,16a-dihydroxy-2l-acetoxy-4,4,14a-trimethyl-A -5wpregnadiene-2O-0ne (LXLII) obtained in Example 52, according to the procedures set forth in Example 61, yields 2l-acetoxy-4,4,14a-trimethyl-A'B 5u-pregnadiene-3,16,20-trione (LXLIV) EXAMPLE 64 21-Hydr0xy-4,4,Mot-TrimethyI-A -Sa-Pregnene- 3,20-Di0ne (XXV) To a solution of 45 mg. of the acetate (XXVI) in 20 ml. of methanol is added with stirring under nitrogen 0.2 ml. of 10% oxygen-free potassium carbonate. After two hours at room temperature, 0.02 ml. of glacial acetic acid is added and after the addition of Water the methanol is removed in vacuo. The mixture is then extracted with chloroform, the chloroform extract washed With Water and chloroform are a as water, dried over sodium sulfate and evaporated to dryness in vacuo to yield a residue of the 21-alcohol (XXV).

EXAMPLE 65 Treating the 21-acetoxy-4,4,l4oz-trimethyl-A -5arpregnene-3,16,20-trione (LXIX) obtained in Example 62 according to the procedures set forth in Example 64, yields 21-hydroxy-4,4,l4a-trimethyl A -5u pregnene 3,16,20- trione (LXX).

EXAMPLE 66 Treating the 21-acetoxy-4,4,14a-trimethyl-A -5apregnadiene-3,16,20-trione (LXLIV), obtained in Example 63, according to the procedures set forth in Example 64 yields 21-hydroxy-4,4,14a-trimethyl-A -Su-pregnadiene-3, 16,20-trione (LXLV) EXAMPLE 67 21-A cet0xy-4,4,14a-Trimethyl-A' -5a.-Pregnene- 3,20-Dione (XX VIII Following the procedure of Example 61 but substituting 6 mg. of the 21-acetate (XXIII) for the 21-acetate (XIX), 21 acetoxy 4,4,14u trimethyI-A' -Saregnene- 3,20-dione (XXVIII) is obtained.

EXAMPLE 68 Treating the 3p,16a-dihydroxy-21-acetoxy-4,4,14ot-trimethyl-N-5oc-pregnene-20one (LXVIII) obtained in Example 60 according to the procedures set forth in Example 61 yields 21-acetoxy-4,4,14a-trimethyl-A -5u-pregnene- 3,16,20-trione (LXXI).

EXAMPLE 69 21-Hydroxy-4,4,14urTrimethyZ-N-Sa-Pregnene- 3,20-Dione (XX VII Following the procedure of Example 27 but substituting 45 mg. of the acetate (XXVIII) for the acetate ()QWI), 21-hydroxy-4,4,14a-trimethyl N-Sa-pregnene-S,ZO-dione (XXVII) is obtained.

The free 21-hydroxy compounds (XXV) and (XXVII) can be converted to any other 21-ester of this invention by substituting the desired 21-hydroxy compound for the diol (XVII) in the procedure of Example 20 and any desired acylating agent for the acetic anhydride. Thus propionic anhydride gives the 21-propionic acid ester derivatives; butyric anhydride, the 21-butyric acid ester derivatives; benzoyl chloride, the 21-benzoic acid ester derivatives; and cyclohexane carbonyl chloride, the 21- cyclohexane carboxylic acid ester derivatives.

EXAMPLE 70 Treating the 21-acetoxy-4,4,14a-trimethyl-A' -5u-pregnene-3,l6,20-trione (LXXI) obtained in Example 68, according to the procedures set forth in Example 64 yields 21-hydroxy-4,4,14a-trimethyI-N-Saregnene-3,16, ZO-trione (LXXII).

EXAMPLE 71 3,8-Acet0xy-21-Mesyloxy-4,4,Z4a-Trimethyl-A -5a- Pregnene-ZO-One (XXIX) To a solution of 38 mg. of the Bfi-monoacetate (XX) in 1 ml. of anhydrous pyridine is added at 0 .055 ml. of

Treating the 3,8,16ot diacetoxy-Zl-hydroxy-4,4,l4a-tri- 239 methyl-A 6a-pregnenerZOTOne (LXIII) obtained in Example 49, according to the procedures set forth in Example 71, yields 35,16a-diacetoxy-2l-mesyloxy-4,4,l4a-trimethyl-A 6a-pregnene-ZO-Qne.

EXAMPLE 73 Treating the 3,l6a-diacetoxy-21-hydroxy-4,4,14a-trimethyl-A -5a-pregnadiene-20-one (LXLIII) obtained in Example 50 according to the procedures set forth in Example 71, yields 3,16u-diacetoxy-21-mesyloxy-4,4,14atrimethyl-A 5a-pregnadiene-20 one.

EXAMPLE 74 2 1 -M esy lxy-4,4 ,1 4 a-Tri me thy l-A a-Pregn en e- 3,20-Dione (XXX) Following the procedure of Example 71 but substituting 36 mg. of the 3-ketone (XXV) for the 3-monoacetate (XX), 21 mesyloxy 4,4,14a-trimethy1-A -Sa-pregnene 3,20-dione (XXX) is obtained.

EXAMPLE 75 Treating the 21-hydroxy-4,4,14u-trimethyl-A -5ot-pregnene-3,l6,20-trione (LXX) obtained in Example 65, in accordance with the procedure set forth in Example 71, yields 21-mesyloxy-4,4,14a-trimethyl-A -5a-pregnene-3,16, -trione.

EXAMPLE 76 Treating the 21-hydroxy-4,4,14a-trimethyl-A -50:- pregnadiene-3,16,20-trione (LXLV) obtained in Example 66, according to the procedures set forth in Example 71, yields 21-mesyloxy-4,4,14ot-trimethy1-A' -5ot-pregnadiene-3,16,20-trione.

EXAMPLE 77 SB-Acetoxy-Zl -Mesyl0xy-4,4,14u-TrimethyI-A' -Stx- Pregnene-ZO-One (XXX I Following the procedure of Example 71 but substituting 38 mg. of the 3 fi-monoacetate (XXIV) for the 3-monoacetate (XX), 35 acetoxy-Z1-methyloxy-4,4,Mot-trimethyl-A"-'5a-pregnene-ZO- ne (XXXI) is obtained.

EXAMPLE 78 Treating the 3 8,16a-diacetoxy-21-hydroxy-4,4,14m-trimethyl-A 5a-pregnene-ZO-one (LXVIII) obtained in Example 60, according to the procedures set forth in Example 71, yields 35,16ot-diacetoxy-21-mesyloxy-4,4,14u-trimethyl-A -Sa-pregnene-ZO-one.

EXAMPLE 79 21-Mesyl0xy-4,4,1 4 a-TrimeIhyZ-A' -S a-Pregnene- 3,20-Dione (XXXII) Following the procedure of Example 71 but substituting 36 mg. of the 3-ketone (XXVII) for the 3-monoacetate (XX), 21-mesyloxy-4,4,14a-trimethy1-A' -5a-pregnene-3,20-dione (XXXII) is obtained.

EXAMPLE 80 Treating the 21-hydroxy-4,4,14a-trimethyl-A' -5u-pregnene-3,16,20-trione (LXXII) obtained in Example 70, according to the procedures set forth in Example 71, yields 21-mesyloxy-4,4,14a-trimethyl-A -5 n-pregnene-3,16, 20-trione.

EXAMPLE 81 3,6-Acetoxy-21Jada-4,4,14u-Trimethyl-M-Sa-Pregnene- ZO-One (XXXIII) A solution of 47 mg. of the 21-mesylate (XXIX) and i 120 mg. of sodium iodide in 1.5 ml. of acetone is refluxed 30 EXAMPLE s2 Treating the 3,8,16a-diacetoxy-21-mesyloxy-4,4,14ot-trimethyl-A 6a-pregnene-ZO-one, obtained in Example 72 according to the procedures set forth in Example 81 yields, 35,1611 diacetoxy 21 iodo 4,4,l4oz trimethyl A 5 a-pregnene-ZO-One.

EXAMPLE 83 21-I0d0-4,4,14a-Trimethyl-M-Sa-Pregnene-3,20 Dione (XXXIV) Following the procedure of Example 81 but substituting 45 mg. of the 21-mesylate (XXX) for the 21-mesylate (XXIX), 21-iodo-4,4,14ot-trimethyl-A -5a-pregnene-S,20- dione (XXXIV) is obtained.

EXAMPLE 85 Treating the 21-mesyloxy-4,4,14a-trirnethy1rA -pregnene-3,16,20-trione, obtained in Example 75, according to the procedures set forth in Example 81, yields 21-iodo- 4,4,14 t-trimethyl-n -5a-pregnene-3,16,20-trione.

EXAMPLE 86 3fl-Acet0xy-21-I0d0-4,4,14a-Trimethyl-A -5a- Pregnene-ZO-One (XXX V) Following the procedure of Example 81 but substituting 47 mg. of the 21-mesylate (XXXI) for the 21-mesy1ate (XXIX), 3 B-acetoxy-21-iodo-4,4,14a trimethyl A 5apregnene-20-one (XXXV) is obtained.

EXAMPLE 87 Treating the 3,8,16m-diacetoxy-21-mesyloxy-4,4,14a-trimethyl-N'-5a-pregneue-20-one obtained in Example 78, according to the procedures set forth in Example 81, yields 35,16a-diacetoxy-21-iodo-4,4,14a-trimethyLA' -Sapregnene-ZO-one.

EXAMPLE 88 21 Jada-4,4,14a-TrimeIhyl-A -5a-Pregnene- 3,20-Diane (XXXVI) Following the procedure of Example 81 but substituting 45 mg. of the 21-mesylate (XXXII) for the 21- mesylate (XXIX), 21-iodo-4,4,14a-trimethyl-N-5a-pregnene-3,20-dione (XXXVI) is obtained.

EXAMPLE 89 Treating the 21-mesyloxy-4,4,14a-trimethyl-A' -5ot-pregnene-3,16,20-trione obtained in Example 80, according to the procedures set forth in Example 81, yields 21-iodo- 4,4,14a-trimethyl-A' -5u-pregnene-3,16,20-trione.

EXAMPLE 90 To a solution of 47 mg. of the iodo compound (XXXIII) in 1 ml. of dioxane is added .9 ml. of a 5% sodium bisulfite solution and the resulting mixture refluxed for 1 hour on the steam cone. Water and chloroform are added and after separation of the layers, the chloroform phase is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residual crystalline material (about 25.5 mg.) on recrystallization from methanol furnishes the pure pregnene derivative (XXXVII) possessing the following properties: M.P. about 166-167"; +107 (c., .44 in AER, 5.79, 5.85, 7.97;;

Analysis.-Calcd. for 0 11 0 (400.58): C, 77.95; H, 10.07. Found: C, 76.89; H, 10.16.

31 EXAMPLE 91 Treating the 3,16adiacetoxy-21-iodo-4,4,14u-trimethyl- A' -Socregnadiene 20 one obtained in Example 83, according to the procedures set forth in Example 90, yields 3,16a-diacetoxy 4,4,14ot-trimethyl-A -5a-pregnadiene-ZO-one (LXLVI).

EXAMPLE 93 313-Hydrxy-4A,I4a-Trimethyl-A a-Pregnene-ZO-One (X X X VIII To a solution of mg. of the pregnene 3-acetate (XXXVII) in 4 ml. of 1 N ethanolic KOH is allowed to stand at room temperature for 19 hours. At the end of this period crystals appear in the solution. The mixture is neutralized with 1 N sulfuric acid, diluted with water, the ethanol removed in vacuo and the aqueous suspension extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated to dryness in vacuo. There remains a crystalline residue (about 12 mg.) melting at about 240245 which after recrystallization from acetone furnishes analytically pure XXXVIII melting at about 247-249;

EXAMPLE 94 Treat-ing the 3B,16a-diacetoxy-4,4,14oc-trimethyl-A -5apregnene-ZO-one (LXXIII) obtained in Example 91, according to the procedures set forth in Example 93, yields Sit-hydroxy 4,4,1404 trimethyl-A -5zx-pregnadiene-20- one (LXXIV).

EXAMPLE 95 Treating the 3,16ct-diacetoxy-4,4,14a-trimethyl-A' Sa-pregnadiene-ZO-one (LXLVI) obtained in Example 92, according to the procedures set forth in Example 93, yields 3-hydroxy 4,4,l4u-trimethyl-A' -Sa-pregnatriene-ZO-one (LXLVII).

EXAMPLE 96 4,4,] 4 a-T rimetI1yl-A -5 oz-Pregnene-3,20-Di0ne IX L) To a solution of 12 mg. of the pregnene 3-ol (XXXVIII) in 8 ml. of reagent grade acetone is added with stirring .27 ml. of a solution containing mg. of

chromium trioxide and 32 mg. of sulfuric acid per milliacetone produces the pure 3,20-diketo (IXL) possessing the following properties: M.P. about 203-204";

[a] +l36(c., .52 in chlf.) 51 i. 5- 1 Analysis.-Calcd. for C H O (356.53): C, 80.85; H,

10.18. Found: C, 80.74; H, 10.28.

EXAMPLE 97 Treating the 3/3 hydroxy 4,4,14a trimethyl-A -5apregnadiene-ZO-one (LXXIV) obtained in Example 94 according to the procedures set forth in Example 96 yields 4,4,14oc trimethyl A -5oz pregnadiene 3,20 dione (LXXV).

32 EXAMPLE 9:;

Treating the 3-hydroxy-4,4,14a-trimethyl-A' -501- pregnatriene-ZO-one (LXLVII) obtained in Example 95, according to the procedures set forth in Example 96, yields 4,4,14a-trimethyl-A -Sa-pregnatritine 3,20 dione (LXLVIII).

EXAMPLE 99 Following the procedure of Example but substituting 45 mg. of the iodo compound (XXXIV) for the iodo compound (XXXIII), 4,4,14a-trimethyl-M-Soc-pregnene- 3,20-dione (IXL) is obtained.

EXAMPLE 100 Treating the 21-iodo-4,4,14a-trimethyl-A' -5a-pregnene- 3,16,20-trione obtained in Example 89 according to the procedures set forth in Example 90 yields 4,4,140t-ll'l: methyl-A -5a-pregnene-3,16,20-trione (LXXVIII).

EXAMPLE 101 .ifi-A cet0xy-4,4,1 4a-Trim ethyl-A 6 a-Pregnene-ZO-One Following the procedure of Example 90 but substituting 47 mg. of the iodo compound (XXXV) for the iodo compound (XXXIII) 3 B-acetoxy-4,4, 14m-trimethyl-A' -5 apregnene-ZO-one (XL) is obtained.

' EXAMPLE 102 3fl Hydroxy-4,4,1 la-Trimethyl-A' -5a-Pregnene-ZO-One (XLI) Following the procedure of Example 93 but substituting 15 mg. of the pregnene 3-acetate (XL) for the preg nene 3-acetate (XXXVII), 3/3-hydroxy-4,4,14u-trimethyl- A' -5a-pregnene-20-one (XLI) is. obtained.

EXAMPLE 104 Treating the 313,16a-diacetoxy-4,4,14u-trimethyl-A -5upregnene-ZO-one (LXXVI), obtained in Example 102 according to the procedure set forth in Example 93, yields 3,8-hydroxy 4,4,l4a trimethyl-A' -5a-pregnadiene-20- one (LXXVII).

EXAMPLE 105 4,4,14a-Trimethyl-A 6a-Pregnene-3,2 O-Dione (X LII Following the procedure of Example 96 but substituting 12 mg. of the pregnene 3-01 (XLI) for the pregnene 3-ol (XXXVIII), 4,4,l4u-trimethyl-A -5a-pregnene 3,20- dione (XLII) is obtained.

EXAMPLE 106 Treating the 3 ,8 hydroxy 4,4,l4u trimethyI-A' -Sapregnadiene-ZO-one (LXXVII) obtained in Example 104 according to the procedures set forth in Example 96 yields 4,4,l4oc trimethyl A -5a pregnadiene 3,20 dione (LXXVIII).

EXAMPLE 107 Following the procedure of Example 90 but substituting 45 mg. of the iodo compound (XXXVI) for the iodo compound (XXXIII), 4,4,14a-trimethy1-A -5a pregnene- 3,20-dione (XLH) is obtained.

EXAMPLE 108 Treating the 21-iodo-4,4,14u-trimethyl-A -Sa-pregnene- 3,16,20-trione obtained in Example 89 according to the procedures set forth in Example 90 yields 4,4,14a-tr-imethyl-A' -5a-pregnene-3,16,20-trione (LXXVIII).

This invention may be variously otherwise embodied within the scope of the appended claims.

i What is claimed is:

\ steroids of the formulae CH CH wherein each R and R is hydrogen, and taken together R and R is 0x0; and Z is selected from the group consisting of hydrogen, hydroxy and the acyloxy radical 45 of a hydrocarbon carboxylic acid of less than twelve carbon atoms.

2. A compound selected from the group consisting of steroids of the formulae I CHgZ l. 1 3:0 l

CHa

CH CH (IEH Z i 0:0

OH: ROM

CH CH y 1. A compound selected from the group consisting of CIIH Z (311,2 0:0 0:0

z 5 -OR "OR 0: n \l 1! 1 l I 311 R R0 V RO CH3 OQOH I CH3 CH3 011: wherein R is selected from the group consisting of hyf i drogen and the acyl radical of a hydrocarbon carboxylic C=Q acid of less than twelve carbon atoms, and Z is selected I from the group consrstlng of hydrogen, hydroxy and the acyloxy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms. 3. A compound selected from the group consisting of steroids of the formulae CH3 CH3 CH3 CH3 CH3OSO3A.

CHzZ i 0:0 i i 5 (LI? CH3 and CH3 CH3 omosoza CHzOSOzA.

Q CH3 W011i) (ijH Z Y-w Y 0:0 i CH3 CH3 CH3 CH3 (Ill- 1080213. omosom ROW CH3 CH3 CH3 CH3 and wherein Y is selected from the group consisting of 0x0 and the acyloXy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms; and A is selected CH3 from the group consisting of lower alkyl and tolyl.

35 4. A compound selected from the of steroids of the formulae group consisting g 05 Yo 2.

C CH3 CQCH (IlHzI (EH21 C=O C=O A --Y Q! I i and Y Y- CH3 CH3' CH3 CH3 wherein Y is selected from the group consisting of 0x0 and the acyloxy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms.

5. 21-hydroxy-4,4,l4-trimethyl-A -5a-pregnene-3,20-dione.

6. 21-acetoxy-4,4,14-trimethyl-A -5a-pregnene-3,20-dione.

7. 4,4,14-trimethyl-A -5a-pregnene 3,20-dione.

8. 2l-hydroxy-4,4,14-trimethyl-A' -5oc-pregnene-3,20-dione.

9. 2l-acetoxy-4,4,14-trimethyl-A -5a-pregnene-3,20-dione.

10. 4,4,14-trimethyl-AL5a-pregnene-3,20-dione.

11. 21 hydroXy 4,4,14-trimethyl-A -Sa-pregnadiene-3,20-dione.

12. 21 acetoxy-4,4,14-trimethyl-A' -5a-pregnadiene-3,20-dione.

13. 4,4,14 trimethyl-A -Sa-pregnadiene-3,20-dione.

14. 21 hydroxy 4,4,14-trimethyl-A -5u-pregnadiene-3,20-dione.

15. 21 acetoxy-4,4,14-trimethyl-A -5a-pregnadiene- 3,20-dione. V

16. 21 acetoxy-4,4,14-trimethyl-A -5a-pregnatriene-3,20-dione.

17. 4,4,14 trimethyl-A' -5a-pregnatriene-3,20- dione.

18. An ester of 21-hydroxy-4,4,14a-trimethyl-A -5apregnene-3,20-dione and a hydrocarbon carboxylic acid of less than twelve carbon atoms.

19. A 3-ester of 3fl-24,28-trihydroxy-A -eburicene-21- oic acid and a hydrocarbon carboxylic acid of less than twelve carbon atoms.

20. A compound selected from the group consisting of 35,21-dihydroXy-A -lanostatriene, 3,8,21-dihydroxy A' lanostatriene, 3,B,16a,2l-trihydroxy- A -lanostatriene, 3 3,16a,21-trihydroxy-A statetraene and in the positions selected from the group consisting of the 3, 16 and 21 positions the mono and diesters of each of these with hydrocarbon carboxylic acids of less than twelve carbon atoms.

21. A process for preparing compounds of the formulae .WQU s CH3 CH3 which comprises treating a compound seletced from the group consisting of CH CH3 wherein R is selected from thegroup consisting of hydrogen and acyl wherein the acyl group is of a hydrocarbon carboxylic acid of less than twelve carbon atoms; and B is selected from the group consisting of hydrogen and lower alkyl; with hydrogen chloride.

22. A compound selected from the group consisting of steroids of the formulae 1 CH CH CH CH C 3 CH B B \H/ CH3 R! CH3 CH3 CH R,

C 3 CH3 B B \N/ i OH: R

CQCH

wherein R is hydrogen; R is acycloxy, wherein the acyl radical is from a hydrocarbon carboxylic acid of less than twelve carbon atoms; and B is selected from the group consisting of hydrogen and lower alkyl.

B B (A H C 2 HaC 2 gig; m CH! R R CH CH CH3 CH3 CH3 CH3 R R R CH3 CH3 CH3 CH3 B B l O@ O l 1H em and CH CH3 CH CH3 ii] R R CHs CH3 ga g 1 1 R W 3 C C s CH3 RHzC- H80 B EH H3O B I q R CH; 20

CH3 R R r R- CH3 CH3 R C a CH:

H wherein each R is hydrogen, each R is selected from the group consisting of hydroxy and acyloxy, wherein the acyl radical is of a hydrocarbon carboxylic acid of less R 30 than twelve carbon atoms; and B is selected from the I OH: group consisting of hydrogen and lower alkyl. RI

References Cited in the file of this patent R Rosenthal et al.: Journal of the American Chemical CQCHB Soc. (1962), vol. 84, page 878. 

22. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THE FORMULAE 